Human herpesvirus type 8 (HHV-8; Kaposi's sarcoma associated herpesvirus) is the etiologic agent of Kaposi's sarcoma (KS) as well as multicentric Castleman's disease and body cavity lymphomas. We hypothesize that :CD8 [unreadable] T cell immunity specific for HHV-8 is central to control of HHV-8 infection, and failure of this surveillance mechanism results in development of HHV-8 related disease. We have shown that HHV-8 specific T cell immunity is established after primary HHV-8 infection, and is lower in persons with HIV-1 infection. We propose to extend these studies of the role of T cell responses in HHV-8 infection and disease, and on the underlying mechanisms of induction of anti-HHV-8 T cell immunity. In Aim 1, we will define longitudinal CD8 [unreadable] T cell responses to 7 HHV-8 lytic and latency cycle proteins during primary and persistent HHV-8 infection (case- crossover design), and their role in development of KS (nested case-control design), in HIV-1 negative and positive subjects in the Multicenter AIDS Cohort Study (MACS). This includes assessment of HHV-8 epitope- specific cytolytic activity and gamma interferon production. In Aim 2, we will analyze the mechanisms of induction of anti-HHV-8 T cell immunity at the cellular level. We hypothesize that HHV-8 does not replicate efficiently in antigen-presenting dendritic cells (DC). Therefore, we believe that HHV-8 infected endothelial cells B cells and monocytes serve as major sources of antigen and are processed and presented by DC through alternative HLA class I pathways for activation of anti-HHV-8 CD8 [unreadable] T cells. Because this is central to our understanding of how HHV-8 infection induces immunity, we will assess HLA class I antigen processing and presentation pathways for HHV-8 proteins in immature and mature DC loaded with HHV-8 infected cells, in comparison to direct HHV-8 infection of DC. In Aim 3, we hypothesize that proteins encoded by K3 and K50RF alter activation of anti-HHV-8 T cell responses by modulating HLA class I and other T cell activation proteins on DC. We will therefore characterize the effects of K3 and K5 on activation of naive and memory CD8 [unreadable] T cells by HHV-8 antigen loaded DC. Application of these methodologies for assessing cellular immunity and HHV-8 expression, combined with access to a longitudinal cohort of HHV-8 seroconverters and incident KS cases in the MACS, offer a unique opportunity to advance our understanding of immune correlates of protection against HHV-8 infection. This is important for development of therapies and prophylactic vaccines for HHV-8 infection.